Respiratory Syncytial Virus (RSV) and Metapneumovirus (MPV) and Pneumonia Virus of mice are common cold viruses belonging to the family of paramyxovirus that share target population and represent a major health problem in newborns and immunocompromised patients.
RSV is the major cause of acute respiratory tract disease in infants and adults across the globe. Between 0.5% and 3.2% of children with RSV infection require hospitalization (Thompson, W. W. et al., 2003, JAMA: The Journal of the American Medical Association 289:179-186), and 5% to 10% of children have prolonged severe infection, a factor believed to be predisposing to wheezing and asthma-like symptoms later in childhood. Immunity to RSV appears to be short-lived, thus re-infections are frequent (Ogra, 2003, Paediatric Respiratory Reviews 5 Suppl A:S119-126).
The human MPV was isolated for the first time in 2001 and is now recognized to be the second major cause of acute respiratory tract disease in infants and adults; it is estimated that it infects over 50% of infants by two years of age and almost all children by five years. MPV accounts for roughly 5 to 15% of respiratory disease in hospitalized young children (Alto, 2004, The Journal of the American Board of Family Practice/American Board of Family Practice 17:466-469; Williams et al., 2004, N Engl J Med 350:443-450). Infection with MPV is a significant burden of disease in at-risk premature infants, chronic lung disease of prematurity, congestive heart disease, and immunodeficiency (Martino et al., 2005, Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation 11:781-796).
Co-infections with MPV and RSV may be common given their prevalence and overlapping winter epidemics. Although it is unclear whether synergistic pathology can occur between these two viruses, exacerbations leading to particularly severe respiratory tract disease were observed in some children co-infected with MPV and RSV (Greensill, 2003, Emerging Infectious Diseases 9:372).
RSV, which belongs to the Pneumovirus genus of the subfamily Pneumoviriniae, and MPV, which belongs to the Metapneumovirus genus of the subfamily Pneumoviriniae, have some similarities in their genetic structure, though MPV lacks the non-structural genes NS1 and NS2 found in RSV. The RSV and MPV envelopes contain three virally encoded transmembrane surface glycoproteins: the major attachment protein G, the fusion protein F, and the small hydrophobic SH protein. Although the RSV and MPV envelopes contain proteins that are functionally similar, it is important to note, however, that the F proteins of RSV and MPV share only 33% amino acid sequence identity. Further, antisera generated against either RSV or MPV do not cross-neutralize both viruses (Wyde et al., 2003, Antiviral Research 60:51-59) and so far no monoclonal antibodies have been isolated that are able to cross-neutralize both RSV and MPV.
The RSV and MPV F glycoproteins direct viral penetration by fusion between the virion envelope and the host cell plasma membrane. Later in infection, F protein expressed on the cell surface can mediate fusion with neighboring cells to form syncytia (Collins et al., 1984 PNAS 81:7683-7687). In both cases, the N-terminus of the F subunit that is created by proteolytic cleavage and contains hydrophobic stretch of amino acids, called the fusion peptide, inserts directly into the target membrane to initiate fusion. After binding to the target cell and subsequent activation, the metastable pre-fusion F protein undergoes a series of structural rearrangements that result in the insertion of the fusion peptide into the target cell membrane, followed by the formation of a stable helical bundle that forms as the viral and cell membranes are apposed. These structural changes lead to the formation of a stable post-fusion F protein.
Vaccines for RSV or MPV infection are currently not available. A formalin-inactivated and alum-adjuvanted RSV vaccine (FI-RSV) tested in the 1960s was found to predispose infants for enhanced disease following natural RSV infection leading to high fever and severe pneumonia, resulting in high hospitalization rates and even some fatalities (Fulginiti et al., 1969, American Journal of Epidemiology 89:435-448; Kapikian et al., 1969, American Journal of Epidemiology 89:405-421; Kim et al., 1969, American Journal of Epidemiology 89:422-434). Similarly, formalin-inactivated MPV vaccines showed immune-mediated enhanced disease in young cynomolgus macaques (de Swart et al., 2007, Vaccine 25:8518-8528). Further, antiviral therapies such as Ribavirin have not been proven to be effective in RSV or MPV infection.
Evidence for the role of serum antibodies in protection against RSV virus has emerged from epidemiological as well as animal studies. In infants, titers of maternally transmitted antibodies correlate with resistance to serious disease (Glezen et al., 1981, The Journal of Pediatrics 98:708-715) and in adults incidence and severity of lower respiratory tract involvement is diminished in the presence of high levels of serum RSV neutralizing antibodies (McIntosh et al., 1978, The Journal of Infectious Diseases 138:24-32). A monoclonal antibody, Palivizumab (Synagis), is registered for the prevention of RSV infection in premature newborns. Palivizumab, however, is not always effective in preventing RSV infection and is not effective therapeutically. Further, prolonged pulmonary replication of RSV in the presence of Palivizumab is followed in animals by the appearance of resistant virus strains (Zhao and Sullender, 2005, Journal of Virology 79:3962-3968). Currently there are no monoclonal antibodies for the treatment or prevention of MPV infection.
The lack of a good working animal model for the most severe forms of RSV infection is related to the fact that RSV and MPV are host-restricted Pneumovirus pathogens. The development of new drugs for the therapy of RSV and MPV infections has been hampered by the lack of an animal model able to recapitulate all the symptoms and severity of the human disease. Indeed, RSV and MPV are not a natural mouse pathogen and induce only a limited, minimally symptomatic, and rapidly aborted primary infection in response to a massive, non-physiologic inoculum of the virus. Pneumonia virus of mice (PVM) is a natural rodent Pneumovirus pathogen which belongs to the same family, subfamily and genus (Pneumovirus) of human and bovine RSV. The PVM F protein shares only 40% amino acid identity with human RSV F protein, but has the same genetic organization with the exception of the M2-L overlap which is present in RSV but absent in PVM. The infection by the natural mouse pathogen PVM replicates many of the signs and symptoms of the most severe forms of RSV as it occurs in human infants. PVM infection is characterized by rapid virus replication accompanied by a massive inflammatory response that leads to respiratory failure and death (Rosemberg and Domachowske, 2008, Immunology Letter 118:6-12). PVM infection in mice is therefore considered to be the most relevant animal model of RSV and MPV severe infections of humans.
The lack of preventive treatment for MPV infection and of vaccines against RSV and MPV infections as well as the therapeutic inefficacy of Palivizumab, highlight the need for new preventive and therapeutic agents against these prominent human pathogens. Given the large prevalence and the possibility of co-infection, it would be highly desirable to have a single agent that is capable of preventing as well as treating or attenuating both RSV and MPV infection and to have an animal model in which to test the agent. Therefore, there is a need for broadly cross-reactive neutralising antibodies that protect against a wide range of paramyxoviruses, for example, at least RSV and MPV, and preferably RSV, MPV and PVM.